Treatments for Parkinson's disease (PD), although effective, do not halt the progressive loss of substantia nigra dopaminergic neurons. Eventually, clinical symptoms become resistant to treatments relying on the integrity of nigrostriatal neurons, such as L-DOPA [S. Mandel et al., Neuroprotective strategies in Parkinson's disease: an update on progress, CNS Drugs, 17:729-762 (2003)]. Preserving viable nigrostriatal neurons would delay disease progression and thus prolong treatments' efficacy [J. H. Kordower et al., Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease, Science, 290:767-773 (2000); D. Kirik et al., Long-term rAAV-mediated gene transfer of GDNF in the rat Parkinson's model: intrastriatal but not intranigral transduction promotes functional regeneration in the lesioned nigrostriatal system, J. Neurosci., 20:4686-4700 (2000); D. L. Choi-Lundberg et al., Dopaminergic neurons protected from degeneration by GDNF gene therapy, Science, 275:838-841 (1997); M. G. Castro et al., Gene therapy for Parkinson's disease: recent achievements and remaining challenges, Histol. Histopathol., 16:1225-1238 (2001)]. Glial-cell-derived neurotrophic factor (GDNF) protects nigral dopaminergic cell bodies and their striatal axon terminals from in vitro and in vivo neurotoxicity induced by 6-hydroxydopamine (6-OHDA) [D. L. Choi-Lundberg et al., Dopaminergic neurons protected from degeneration by GDNF gene therapy, Science, 275:838-841 (1997)4], MPTP [J. H. Kordower et al., Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease, Science, 290:767-773 (2000)], or methamphetamine [W. A. Cass, GDNF selectively protects dopamine neurons over serotonin neurons against the neurotoxic effects of methamphetamine, J. Neurosci., 16:8132-8139 (1996)], and possibly also in PD patients [S. S. Gill et al., Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease, Nat. Med., 9:589-595 (2003)].
GDNF has been delivered into the brain using adenovirus (RAd)-, adeno-associated virus-, herpes simplex virus type 1 (HSV-1)-, or lentiviral-derived vectors or by direct peptide injection [M. G. Castro et al., Gene therapy for Parkinson's disease: recent achievements and remaining challenges, Histol. Histopathol., 16:1225-1238 (2001); S. S. Gill et al., Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease, Nat. Med., 9:589-595 (2003); A. Bjorklund et al., Towards a neuroprotective gene therapy for Parkinson's disease: use of adenovirus, AAV and lentivirus vectors for gene transfer of GDNF to the nigrostriatal system in the rat Parkinson model, Brain Res., 886:82-98 (2000); E. A. Burton et al., Gene therapy progress and prospects: Parkinson's disease, Gene Ther., 10: 1721-1727 (2003)]. Despite its neuroprotective actions, GDNF can have untoward effects (i.e., reduction of tyrosine hydroxylase mRNA in nigrostriatal neurons, aberrant morphologies of striatal tyrosine hydroxylase-immunoreactive axons, and increased cell death following experimental stroke) [B. Georgievska et al., Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer, Exp. Neurol., 177:461-474 (2002); A. Arvidsson et al., Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats, Neurobiol. Dis., 14:542-556 (2003); C. Rosenblad et al., Long-term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system, Eur. J. Neurosci., 17:260-270 (2003)].
The disclosures of all documents referred to throughout this application are incorporated herein by reference. The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the drawings.